This invention relates to the separation of enantiomers or a racemic mixture, into the specific isomers.
Stereoisomers are those molecules which differ from each other only in the way their atoms are oriented in space. Stereoisomers are generally classified as diasteromers or enantiomers; the latter embracing those which are mirror images of each other, the former being those which are not. The particular arrangement of atoms that characterize a particular stereoisomer is known as its optical configuration, and are generally identified as either + or xe2x88x92 (also D or L) (and d or l) or R or S.
Though differing only in orientation, the practical effects of stereoisomerism may be important. For example, the biological and pharmaceutical activities of many compounds are strongly influenced by the particular configuration involved. Many compounds are only of widespread utility when provided in a given stereoisomeric form. Therefore, it is the separation of enantiomers that presents a special problem because their physical properties are identical. This is particularly true when involving a racemic mixture; that is, a mixture that comprises equal amounts of enantiomers having different optical configurations. Separation of the racemate into its respective enantiomers, generally known as a resolution, is, therefore, a process of considerable importance and challenge.
A number of techniques for separating enantiomers are known in the art such as various chromatographic methods or enzyme-catalyzed reactions. Most, however, are useful for obtaining small analytical quantities and are not practical for separating larger quantities for commercial purposes. One such method is known as an indirect separation which involves reacting the enantiomers with an optically pure chiral derivatizing agent. A direct method of separation is much like the indirect method involving the formation of a diasteromeric species which is transient, with the stability of one species differing from the other.
Another method described in U.S. Pat. Nos. 4,800,162 and 5,077,217 utilizes multi-phase and extractive enzyme membrane bioreactors for the resolution of racemic mixtures of optically active compounds.
Liquid membranes have been used for separating enantiomers as discussed in the book Chiral Separation, Applications and Technology, S. Ahuja, Editor; American Chemical Society, 1997, Chapter 11, pp. 309-334. One system is described on pp. 329-330, where two membrane modules are employed.
U.S. Pat. No. 5,080,795 to Pirkle et al. employs a similar supported chiral liquid membrane and a chiral carrier which selectively complexes with one of the two enantiomeric optical configurations. However, the liquid membrane present in the Pirkle et al. patent is used in a totally different manner so that in fact the apparatus is in effect a contactor rather than a liquid membrane. The disclosed apparatus has a different principle of operation and different engineering basics compared to the apparatus employed in the present invention. As is clearly shown in the Pirkle et al. patent, the liquid membrane must flow from the source phase containing the feed liquid to the receiving phase containing the solution enriched with one enantiomer. In that respect, the method of separating enantiomers disclosed by Pirkle et al. is totally different from the method of this invention.
Thus, although liquid membranes have been known to be useful in separating chiral enantiomers, they have never been used commercially because, depending on the design and the materials used, the separation modules or parts thereof deteriorate rather quickly or the necessary ingredients such as the liquid membrane or the carrier are partially lost in the process and the separation must be periodically interrupted to replace or replenish them. Furthermore, the prior art methods are often batch processes and, even if continuous, could not be adapted for a large scale continuous separation. Such processes do not provide the necessary rate of transport and the degree of separation in a reasonable time period to make them feasible for large scale commercial enantiomer separation. These deficiencies are resolved and eliminated by the method of this invention.
The present invention is directed to a method for separating or resolving enantiomers in a supported liquid membrane module which comprises a liquid membrane, feed fluid containing a racemic mixture and a sweep fluid into which the separated enantiomer passes, such that said feed fluid and said sweep fluid are adjacent to, but on opposite sides of, said liquid membrane and the feed fluid and the sweep fluid have a substantially continuous interfacial contact along the length of the liquid membrane, said method comprising:
a) contacting liquid membrane with said feed fluid;
b) transporting preferentially one enantiomer from the feed fluid into the liquid membrane;
c) contacting liquid membrane with said sweep fluid;
d) transporting the enantiomers from the liquid membrane into the sweep fluid; and
e) recovering the enantiomers from the sweep fluid.
The feed fluid may be composed only of the enantiomers or optionally it may also contain a solvent. If the enantiomers are solid, then a solvent must be employed to dissolve the solid enantiomers. If the enantiomers are liquid, a solvent is usually not absolutely necessary but it may be desirable to employ a solvent. If the selectivity of one enantiomer by the liquid membrane is high, then substantially only one isomer will transport through the membrane and the separation of the isomers will be substantially complete. Optionally, the liquid membrane may also contain a phase transfer agent (PTA) which can be any chemical agent to aid the partitioning of an enantiomer from the feed fluid into the liquid membrane. The feed fluid pH could be adjusted to favor the solubility of the enantiomers in the liquid membrane. Likewise, the sweep fluid pH could be adjusted to favor the solubility of the enantiomers in the sweep fluid.
The solvent that may be employed in the feed must dissolve the enantiomers but it must be different than the solvent in the liquid membrane and it must be substantially immiscible with the liquid membrane. Nevertheless, the solvent could be the same as the solvent in the sweep.
Those skilled in the art will be informed what solvents could be used for a particular enantiomer and the literature provides much information in this regard. For example, a discussion is provided in Chiral Separations, S. Ahuja, ed., (1996) p. 283.
A membrane is a semi-permeable barrier that spatially divides two solutions of different concentrations and controls the solute exchange rate between them. A liquid membrane can serve as a membrane between two other liquid phases provided it is immiscible with those liquid phases. The liquid membrane in the invention consists of a liquid that is immiscible with the feed and the sweep fluids and preferentially dissolves the enantiomer that is to be isolated. The liquid membrane optionally may also contain a carrier and a phase transfer agent (PTA). The need for a carrier and a PTA will depend on the enantiomers that are being separated, the degree of solubility of the desired enantiomer in the liquid membrane (i.e., the solvent present in the liquid membrane), the enantios electivity and the flux rate across the membrane.
A chiral carrier is a material that enhances the rate of selective transport of an enantiomer. Generally, a chiral carrier complexes preferentially with one enantiomer in the liquid membrane or dissolves preferentially one enantiomer. In effect, the carrier increases the solubility of one enantiomer in the liquid membrane. This facilitates the transport of the complexed or the preferentially soluble enantiomer through the liquid membrane. Thus, a solvent used as a liquid membrane could conceivably act as a carrier. The uncomplexed carrier and the carrier complexed with an enantiomer should be substantially immiscible with the feed and sweep fluids. The carrier, if present, must have a degree of solubility in the solvent which constitutes the major portion of a liquid membrane. It is preferable that the carrier have substantial solubility in the solvent and it is further preferable that it be close to its maximum concentration in the liquid membrane. Generally the greater the concentration of the carrier, the greater the flux. For practical reasons, however, there will be an optimum range of the concentration to provide good flux without increasing the cost unreasonably. The topic of flux and related subjects are discussed in Cussler E. L., xe2x80x9cDiffusion: Mass Transfer in Fluid Systems,xe2x80x9d Cambridge University Press (1984 ed.), pp. 395-400.
The literature generally contains much information regarding the carriers for specific enantiomers. For example, the list in the following Table is illustrative of the literature disclosing appropriate carriers for the indicated enantiomers.
As can be seen in the above Table, for some enantiomers there may be only one known carrier, but for others, there may be a choice of several carriers. Those skilled in the art will understand that chromatography can be used as a screening tool to determine which materials can be used as carriers for specific enantiomers. For example, a prospective carrier is placed in the column packing and a feed fluid containing specific enantiomers is injected into the column. If the column separates the enantiomers, then the test material in the column can be used as the carrier in the method of this invention. If the carrier is a solid, then a solvent must be employed to dissolve the carrier. The solvent may be achiral or chiral. But the carrier itself must be chiral because it must have preference for one enantiomer over the other.
As mentioned above, PTA must not necessarily be included in the liquid membrane, but it may be advantageous to have a PTA present. The phase transfer agent (PTA) in general is a non-covalent molecular associate of a specific substrate which drastically alters the solubility profile of the substrate. Examples of this are (a) for an ionic substrate, a large counter ion that will form an ion pair with the ionic substrate, causing the ion pair to be soluble in a media in which the original ion is not soluble; (b) for a non-ionic substrate, a PTA might engage in a weak interaction with the non-ionic substrate or may complex with such substrate with the result that the resulting substrate has a qualitatively different solubility property than the original substrate. In nature, all the protein carriers in a human or animal body act as PTAs.
The amount of a PTA used in a liquid membrane will depend on its ability to complex and to transport an enantiomer. As an example, the concentration of a PTA may range from an extremely minor amount such as 0.1 mmole up to 10 mmoles, or even up to 100 mmoles and in the case of an ionic PTA, it could even approach 1 mole. The discussion of the use of PTA may be found in the publication of Pirkle et al., xe2x80x9cUse of Achiral Ion-Pairing Reagents With Chiral Stationary Phasesxe2x80x9d, J. of Chromatography, 479 (1989), pp. 377-386.
If neither a carrier nor a PTA is employed, a separation is possible only if the solvent has selectivity for one enantiomer over the other. However, if both enantiomers are equally soluble in that solvent, then no separation is possible without a carrier. If the solvent is chiral, then generally one enantiomer will be preferentially soluble in such a chiral solvent. For example, if Nopol is used as a liquid membrane, then one enantiomer from a mixture of amino acid enantiomers will be transported substantially faster than the other enantiomer through such a liquid membrane and separation will occur even without a carrier (Bryjak et al., J. Memb. Sci., 85, 221, 1993. If, however, achiral liquid membrane is employed, generally no separation of enantiomers will occur without the use of a carrier or a PTA.
The sweep fluid, sometimes also referred to as the strip or purge fluid, is the fluid into which preferentially one enantiomer passes from the liquid membrane. The sweep fluid is generally a liquid consisting of a solvent and optionally an enantiomer solubility enhancer, a material that would aid the release of the enantiomer from the carrier in the liquid membrane. Such a material can also strongly increase the solubility of the enantiomer in the sweep. Examples of solubility enhancers include acids and bases to alter the pH of the sweep. The solvent in the sweep must be different than the solvent in the liquid membrane but it can be the same as the solvent in the feed fluid. It could be chiral or achiral. The solvent in the sweep must be substantially immiscible with the liquid membrane. The pH of the sweep and also of the feed fluid can be adjusted by using an appropriate buffer to maximize the solubility of one enantiomer or to provide a pH gradient between the feed and the sweep to favor active transport of the enantiomer from the feed to the sweep fluid. For example, in the separation of the racemic mixture of N-(3,5-dinitrobenzoyl) leucine, the sweep is water. Potassium dihydrogen phosphate, KH2PO4, is used as a buffer to adjust the pH. Generally it is preferable to adjust the pH of the sweep to maximize the solubility of one enantiomer in the sweep.
In the present invention, the liquid membrane may be stationary or it may be moving or flowing from one location to the other. The two locations, however, are anywhere where there is no area for mass transfer between the first location and the second location. That means, it could be flowing anywhere where the liquid membrane is not directly between the feed and the sweep fluids. The flow of the liquid membrane may be in any direction or stationary. Even if one or both of the fluids and the liquid membrane are stationary, the enantiomers can still be transported across from the feed fluid through the liquid membrane, and into the sweep fluid. This transport occurs if the concentration of the enantiomer is higher in the feed fluid relative to the sweep, or there is active transport by coupled facilitated diffusion. The literature defines conditions when these occur, e.g. E. L. Cussler, xe2x80x9cDiffusion: Mass Transfer in Fluid Systems,xe2x80x9d Cambridge University Press (1984 ed.), p. 402. It is generally preferable that the fluids be moving, either in the same direction or in the opposite direction. A diagrammatic illustration of the relative locations of the various fluids and a specific example of the flow of the fluids is shown in FIG. 1a. 
It should be understood that the walls of the liquid membrane contain pores. These pores are always filled with one of the fluids present in the module, i.e., the feed fluid, liquid membrane fluid or sweep fluid. It is a preferred feature of this invention to have a particular type of a fluid in the pores depending on the level of partitioning of the enantiomers or enantiomers. For enantiomers that have poor partitioning into the liquid membrane, the pores of the fiber walls of the liquid membrane should preferably be filled with the feed and/or sweep fluids because the enantiomers are more soluble in the feed and the sweep than in the liquid membrane and it is desirable that the concentration of the enantiomer be as high as possible in the walls.
For enantiomers that have high or good partitioning in the liquid membrane, i.e., enantiomers more soluble in the liquid membrane solvent then in the feed or sweep fluids, the walls preferably should be filled with the liquid membrane. When the pores of the fiber is filled with a particular fluid, it may be said that the fiber walls are wetted with that fluid. It is more common that the majority of enantiomers have poor partitioning into the liquid membrane. In such cases, it is preferable that the fiber material for tubular membranes be chosen so that the pores of the fibers are filled with the feed and sweep fluids. Spacers are required to ensure that there is no contact between the inner and the outer fiber, that is, so that there is no direct contact between the feed and the sweep fluids.
Any enantiomers may be separated employing the method of this invention, regardless of the chemical nature of the enantiomers. Thus, optically active organic amines, amides, nitrites, carboxylic acids, esters, alcohols, hydantoins and other optically-active compounds may be separated into the individual enantiomers. The separated enantiomers may be useful in pharmaceuticals, agricultural, chemicals, fragrances, flavoring agents and other applications.
The method of this invention is particularly useful in separating enantiomers on a commercial scale because the separation is efficient and economical. All parts of the module are of a substantially permanent nature and are not used up, requiring frequent interruption in the operation for the purpose of replacing any used-up parts. Furthermore, the separation could be carried out in a continuous process. The actual rate of separation will depend on the specific enantiomers being separated, the solvents used, the carrier and PTA used, the size of the unit, the degree of buffering and the temperature at which separation is conducted.
The separation of enantiomers described above may be accomplished in a tubular or hollow liquid membrane module that is particularly effective on a commercial scale. The liquid membrane can be stationary or moving, although the latter is preferred. The module has a housing which is adapted to contain at least one tubular liquid membrane element. The element includes a first tubular membrane located within a second tubular membrane with an annular gap defined between the first tubular membrane and the second tubular membrane. The first (inner) tubular membrane, which generally may have an inside diameter (I.D.) of about 50 microns to about 2 mm and wall thickness of 10 microns to 500 microns, is longer than the second tubular membrane so that its ends extend axially out of the ends of the second tubular membrane. The outer tubular fiber may generally have I.D. of about 100 microns to about 3 mm with the same wall thickness as the thinner tube. Also, a screen spacer/support may be used in the annular space or gap between the inner and outer tubes to provide mechanical support for the tubular membranes. The liquid membrane is housed or contained in the annular space and as the liquid flows, the spacers/screens create mixing of the liquid membrane. Spacers can be made from any material such that it prevents direct contact between the inner and outer fiber along the length of the fiber. The annular space is generally from about 10 microns to about 500 microns but typically between about 20 and 50 microns. Generally, smaller annular spaces and thinner wall thicknesses of the tubular membrane are preferred because this creates less resistance to diffusion. The membranes are 20% to 80% porous and more typically about 30% to 50%. The pore sizes in the membranes are between about 0.01 microns to about 10 microns but the smaller pores are preferred if a high pressure drop is applied between the feed and sweep fluids. The overall size of the module is application dependent. A module must contain at least one set of membranes (one inner and one outer tubular membrane) but it may contain hundreds or thousands of them. The more membrane sets, the larger the volume of enantiomers that may be separated per unit time. Thus, the module size may be 10-12 inches in diameter and up to about 3 feet long. There is a theoretical limit to the size of the module if good separation of enantiomers is to be maintained.
The lumen of the first tubular membrane is used as fluid passage for the feed fluid, and the outer surface of the second tubular membrane is used as fluid flow surface for the sweep fluid. Alternatively, the lumen of the first or inner tubular membrane can be used as the fluid passage way for the sweep fluid and the outer surface of the second or outer tubular membrane can be used for the passage of the feed fluid.
The module also includes four tube sheets, two at each end of the housing. At one end of the housing, a first tube sheet extends between the housing and the exterior surface of the first end of the first (inner) tubular membrane, and the second tube sheet extends between the housing and the exterior surface of the first end of the second (outer) tubular membrane. The space between the first and second tube sheets is used as a membrane liquid intake manifold for providing a membrane liquid from a membrane liquid inlet port on the housing to the annular gap.
At the other end of the housing, a third tube sheet extends between the housing and the exterior surface of the second end of the first tubular membrane, and fourth tube sheet extends between the housing and exterior surface of the second end of the second tubular membrane. The space between the third and fourth tube sheets is used as a membrane liquid outlet manifold for removing a membrane liquid from the annular gap at a membrane liquid outlet port on the housing.
The space between the first tube sheet and the housing is used as a feed intake manifold for providing a feed fluid from a feed fluid inlet port in the housing to the fluid passage way. Likewise, the space between the third tube sheet and the other end of the housing is used as a feed fluid outlet manifold for removing a feed fluid from the fluid passage way to a feed fluid outlet port in the housing.
A sweep fluid inlet port is formed in the housing between the second tube sheet and a fourth tube sheet. This port facilitates the introduction of a sweep fluid from a sweep fluid to the fluid flow surface. The sweep fluid outlet port is located on the other side of the housing, spaced from the sweep fluid inlet port. The sweep fluid outlet port facilitates the removal of the sweep fluid from the fluid flow surface at a sweep fluid outlet port on the housing. As already mentioned above, the conduits for the feed and sweep fluids may be interchanged. If the enantiomers are gaseous, the module may also be operated when the sweep fluid is in gas phase. In such a module, the sweep fluid inlet port is closed and a vacuum pump and/or a condenser is connected to the sweep fluid outlet port to draw the enantiomer out of the module from the enantiomer-enrichment channels. Alternatively, a sweep fluid may be used to remove the separated enantiomer.
In addition, the Tubular or Hollow Fiber module includes various connections to the element for providing independent and simultaneous flowing of a feed fluid through the fluid passageway, a membrane liquid through the membrane liquid passageway, and a sweep fluid upon the fluid flow surface. These connections include differential pressure controllers, fluid pumps, and a membrane liquid reservoir.